UT Southwestern geneticists identify new mechanism for nonalcoholic fatty liver disease absent obesity

Using a genetic screening platform developed by a UT Southwestern Nobel Laureate, scientists with the Center for the Genetics of Host Defense at UT Southwestern Medical Center have identified genetic mutations that contribute to nonalcoholic fatty liver disease (NAFLD), providing a potential future target for therapeutic interventions.

While obesity and diabetes are well-known risk factors for fatty liver disease, the UT Southwestern researchers were able to identify a new cause of fatty liver disease absent obesity – a reduction in the level of Predicted gene 4951 (Gm4951), which in turn leads to non-alcoholic fatty liver disease. Currently there are no approved medications or treatments for the disease, which is rapidly emerging as a major cause of chronic liver disease in the United States. Identifying the role of this gene in the development of the disease provides an important new direction for those studying the disease to find potential treatments.

“We identified a rare non-obese mouse model of NAFLD caused by GM4951 deficiency. This study lays the groundwork for the future development of approaches to activate the human Gm4951 homolog to combat NAFLD,” said lead author Zhao Zhang, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and the Division of Endocrinology in Internal Medicine. The findings appear in Nature Communications.

The Center for the Genetics of Host Defense is directed by Bruce Beutler, Ph.D., a Regental Professor and one of four Nobel Laureates at UT Southwestern. Dr. Beutler received the 2011 Nobel Prize in Physiology or Medicine for discovering an important family of receptors that allow mammals to sense infections when they occur, triggering a powerful inflammatory response. Dr. Beutler also developed the largest mouse mutagenesis program in the world, along with a forward genetic screen platform that allows researchers in the Center to screen for more than half of all genes in the mouse genome. Along with a means of instantly identifying mutations responsible for both quantitative and qualitative phenotypes, the program allows for rapid discovery of many new components of the immune system.

“This study identified a potential human homolog of mouse GM4951 and the interaction of GM4951 with another human NAFLD/NASH associated protein HSD17B13, suggesting the discovery is likely conserved in humans,” said Dr. Zhang, whose lab is working to understand the molecular mechanism of metabolic diseases, with the underlying aim of translating this knowledge into novel therapeutic strategies.

The current study is built on the forward genetic screen platform, which allowed the researchers to identify two semi-dominant allelic missense mutations (Oily and Carboniferous) of Gm4951 and define a critical role for GTPase-mediated translocation in hepatic lipid metabolism. Among their findings, the researchers found that loss of GM4951 causes NAFLD without obesity, that GM4951 promotes lipid oxidation to prevent lipid from accumulation in the liver and that GM4951 functions as a GTPase to translocate HSD17B13 to lipid droplets.

GM4951 is a poorly characterized protein and this study defined the role of GM4951 as a GTPase involved in lipid oxidation, said Dr. Zhang. The GM4951-deficient mice developed nonalcoholic fatty liver disease on a high-fat diet with no changes in body weight or glucose metabolism, the researchers noted.

The research is supported by NIH grants R00DK115766 and R01DK130959 to Dr. Zhang; NIH grants R01AI125581 and U19AI100627 to Dr. Beutler; funding from the Lyda Hill Foundation to Dr. Beutler, and partially through a sponsored research agreement from Pfizer, Inc. to Dr. Beutler.

An estimated one-quarter of adults in the U.S. have nonalcoholic fatty liver disease (NAFLD), an excess of fat in liver cells that can cause chronic inflammation and liver damage, increasing the risk of liver cancer, liver failure and need for transplant. NAFLD has become the most common cause of liver disease worldwide.  In recent decades, it has been suggested that changes in the lifestyles clearly drive the risk in the prevalence of NAFLD. However, hepatic fat content varies substantially among individuals with equivalent adiposity, indicating that genetic factors contribute to the development of NAFLD. Dr. Zhang’s lab is investigating more than 20 genes in which mutations affect liver triglyceride with no change in body weight to identify new mechanisms of NAFLD.

UT Southwestern has multiple lines of investigation into the unknown causes of non-alcoholic fatty liver disease as well as potential treatments. Among them:

• A groundbreaking 2008 study by Drs. Helen Hobbs and Jonathan Cohen, who run a joint laboratory in the Eugene McDermott Center for Human Growth and Development arose from the Dallas Heart Study and unearthed a genetic basis for the risk of developing NAFLD. The study found that a variation in the PNPLA3 gene can make people more susceptible to developing fatty livers and progressing to NAFLD, and that while the troublesome gene variant is uncommon in African-Americans, almost half of Hispanics have it. The findings mirrored and helped explain the differences in NAFLD observed in the clinic between those two groups. In 2017,the two reported how obesity significantly amplifies the effects of three gene variants that increase risk of nonalcoholic fatty liver disease by different metabolic pathways.
• Investigations by Dr. Jay Horton, Director of UT Southwestern’s Center for Human Nutrition showed that deleting a protein known as Scap reduced fat production and prevented fatty liver disease in mice despite obesity, high-fat diets, and high blood sugar. This occurred, Dr. Horton reported, because without Scap, the mice could not make the SREBPs involved in lipid manufacture and storage. He later reported that liver fat can be reduced in humans with fatty livers by inhibiting two enzymes involved in making fatty acids — acetyl-CoA carboxylase 1 and 2. While that inhibition was associated with increased triglyceride levels in the blood, there are ways to prevent or treat that condition.
• UT Southwestern researchers in the Liver and Digestive Diseases division have been involved in clinical trials evaluating potential pharmaceuticals such as Emricasan, an anti-inflammatory drug with fast-track designation by the FDA for the treatment of non-alcoholic steatohepatitis cirrhosis. TARGET-NASH is a longitudinal observational cohort study of patients being managed for NASH and related conditions across the entire spectrum NAFLD in usual clinical practice. TARGET-NASH is a research registry of patients with NAFL or NASH within academic and community real-world practices maintained in order to assess the safety and effectiveness of current and future therapies.
• UT Southwestern scientists in the Division of Digestive and Liver Disease and UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center recently developed a simple blood test to predict which NAFLD patients are most likely to develop liver cancer. Studies have found that people with NAFLD have up to a 17-fold increased risk of liver cancer. For NAFLD patients believed to be most at risk of cancer, doctors recommend a demanding screening program involving a liver ultrasound every six months. But pinpointing which patients are in this group is challenging and has typically involved invasive biopsies.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.